CN110642766B - Monoamine oxidase A inhibitor - Google Patents
Monoamine oxidase A inhibitor Download PDFInfo
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- CN110642766B CN110642766B CN201910818696.1A CN201910818696A CN110642766B CN 110642766 B CN110642766 B CN 110642766B CN 201910818696 A CN201910818696 A CN 201910818696A CN 110642766 B CN110642766 B CN 110642766B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
Abstract
The invention discloses a monoamine oxidase A inhibitor, which is obtained by catalyzing thioether synthesis at room temperature by using cheap ruthenium carbon as a catalyst, and specifically comprises the following steps: the compound shown as the formula (III) is used as a reaction raw material, Ru/C is used as a catalyst, and NaIO is added4The method is characterized in that the method is carried out at room temperature by taking water as a solvent as an oxidant, and after the reaction is finished, the reaction solution is subjected to post-treatment to obtain the sulfone compound shown in the formula (IV). According to the method, water is used as a solvent, and cheap ruthenium carbon is oxidized by sodium periodate to generate ruthenium tetroxide, so that a target product is further synthesized by oxidizing a thioether compound, and the preparation method is more efficient, quicker, environment-friendly and mild. The prepared monoamine oxidase A inhibitor has good monoamine oxidase A inhibition activity, can be used for preparing medicines for inhibiting the monoamine oxidase A activity, has wide application prospect in medicine development, and provides a more effective way for treating related diseases.
Description
(I) technical field
The invention relates to a monoamine oxidase A inhibitor, a synthesis method and application thereof.
(II) background of the invention
The sulfone compound is a very important organic synthesis intermediate, has very wide application in the aspects of medicinal chemistry, material science and wide bioactivity. For example, bicalutamide (structure a) is an anti-androgen drug, and is suitable for treating advanced prostate cancer; laropilan (structure b) is a commonly used cardiovascular drug for the treatment of lipodystrophy; rofecoxib (structure c) is a cyclooxygenase selective inhibitor, can be used for treating arthritis and relieving pain, has good patient tolerance, and also has potential clinical value and therapeutic effect in preventing carcinoma of large intestine and esophageal cancer, and treating head and neck cancer, breast cancer, bladder cancer and cervical cancer; has certain bacteriostasis effect than dapsone (structure d) and is often used for treating leprosy. Meanwhile, the sulfone compound also plays a very important role in agricultural chemicals, for example, mesotrione (structure f) is a common herbicide, and has the advantages of no influence on the environment, no influence on the pesticide effect due to rainfall and the like. Meanwhile, sulfide oxidation is the basis of catalytic oxidative desulfurization of crude oil, wherein sulfur compounds are removed, which is also one of the most common difficulties.
Ruthenium tetroxide has been widely used in oxidation reactions since Djerassi reported in 1953 as an oxidant for use in chemical reactions. However, ruthenium tetroxide has the disadvantages of unstable property, high toxicity, high price and the like, which has certain limitations on chemical research. Therefore, it becomes crucial to find a more green, inexpensive, versatile, highly selective process. The method uses sodium periodate to oxidize cheap ruthenium carbon to generate ruthenium tetroxide, thereby further oxidizing the thioether compound to synthesize the sulfone compound.
Monoamine oxidase is a main enzyme participating in monoamine substance metabolism in vivo, monoamine oxidase is divided into A type and B type, metabolic substrates of monoamine oxidase are different, monoamine oxidase activity has a certain relation with body aging and Parkinson's disease, and monoamine oxidase inhibitor is used for treating various diseases which have proved to have obvious effects, such as depression, Parkinson's disease, senile dementia and the like.
Disclosure of the invention
The present invention provides a monoamine oxidase A inhibitor obtained by catalyzing thioether synthesis at room temperature using inexpensive ruthenium carbon as a catalyst. The monoamine oxidase A inhibitor has extremely strong monoamine oxidase A inhibition effect, and is applied to preparation of drugs for inhibiting monoamine oxidase A activity.
The technical scheme of the invention is as follows:
a monoamine oxidase A inhibitor of formula (IV) synthesized as follows:
the compound shown as the formula (III) is used as a reaction raw material, Ru/C is used as a catalyst, and NaIO is added4The method comprises the following steps of (1) reacting at room temperature (20-30 ℃) by taking water as a solvent as an oxidant, and after the reaction is finished, carrying out post-treatment on a reaction solution to obtain a sulfone compound shown as a formula (IV); the amount of the Ru/C is 0.5-2%, preferably 1%, of the amount of the substance of the compound shown in the formula (III) in terms of the amount of the substance of Ru; the NaIO4The amount of the substance(s) is 50 to 150%, preferably 110% of the amount of the substance of the compound represented by the formula (III).
Further, the volume usage amount of the water is 3-5 mL/mmol based on the amount of the compound shown in the formula (III).
The progress of the reaction of the present invention can be monitored by a conventional method, for example, TLC is used to monitor the completion of the reaction of the starting compound represented by formula (III) to determine the time point of the completion of the reaction; the reaction time is usually 2-3 h.
Further, the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, the reaction solution is filtered, washed by dichloromethane, the filtrate and the washing solution are combined, washed twice by saturated sodium chloride solution, and dehydrated by anhydrous sodium sulfate, the solvent is removed by evaporation and dried, and the target product shown in the formula (IV) is obtained.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a monoamine oxidase A inhibitor, which has the advantages of simple preparation process and operation process, nearly 99% yield and simple subsequent treatment, and can obtain a pure product without complicated separation and purification.
(2) Compared with the traditional method, the method takes water as a solvent, uses sodium periodate to oxidize cheap ruthenium carbon to generate ruthenium tetroxide, further oxidizes the thioether compound to synthesize a target product, and is more efficient, quicker, more environment-friendly and milder.
(3) The monoamine oxidase A inhibitor has good monoamine oxidase A inhibition activity, can be used for preparing drugs for inhibiting the monoamine oxidase A activity, has wide application prospect in drug development, and is expected to provide a more effective way for treating related diseases.
(IV) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1: preparation of ether compound III
The reaction formula is as follows:
1.258g (5.0mmol) of Compound II (from Sigma-Aldrich) and 1.382g (10.0mmol) of potassium carbonate were charged into a reaction flask, dissolved in 60mL of acetone, stirred, and 0.576g (5.0mmol) of Compound I (from Sigma-Aldrich) was added thereto, and the reaction was refluxed at elevated temperature for 7 hours. The completion of the reaction of compound II was checked by TLC and the reaction was stopped. The reaction solution was filtered and washed with dichloromethane (50 mL. times.2), and the filtrate and the washings were combined. Washing twice with saturated sodium chloride solution, drying with anhydrous sodium sulfate, evaporating to remove solvent, and separating by column chromatography (mobile phase n-hexane: ethyl acetate: 15: 1) to obtain refined compound III with yield of 77%. The structure of the compound of formula III is characterized as follows:
1H NMR(500MHz,CDCl3)δ7.71-7.25(m,3H),4.28(s,1H),3.79-3.75(m,2H),3.23-3.18(m,2H),3.94-3.61(m,4H),3.17(s,1H),2.47(s,3H).13C NMR(125MHz,CDCl3)δ136.8,133.4,133.2,129.9,128.0,126.4,77.3,73.8,48.9,51.3,32.6,23.4,14.7.GC-MS(EI):m/z285.04[M+].
example 2: preparation of sulfones compound IV
The reaction formula is as follows:
to a reaction flask were added 0.02g of Ru/C catalyst, 470mg (2.2mmol) of sodium periodate, and 4mL of water, and then 285mg (1mmol) of compound III was added to the reaction flask with stirring and reacted at room temperature for 2 hours. The completion of the reaction of the compound III was checked by TLC and the reaction was stopped. The reaction solution was filtered, washed with dichloromethane (15 mL. times.2), and the filtrate and the washings were combined. The reaction mixture was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to give compound IV in 99% yield. The structure of the compound of formula IV is characterized as follows:
1H NMR(500MHz,CDCl3)δ8.29-7.60(m,3H),4.27(s,1H),4.20-4.17(m,2H),3.92-3.88(m,2H),3.56-3.53(m,2H),3.27-3.24(m,2H),3.19(s,1H),3.34(s,3H).13C NMR(125MHz,CDCl3)δ141.7,138.9,134.5,131.0,128.3,126.8,81.5,74.1,57.0,51.4,50.2,47.9,39.5.HRMS(ESI):C13H17ClNO4S2 +for[M+H]+,calculated 350.0282,found350.0277.
example 3: monoamine oxidase A inhibitory Activity test
(1) Sample preparation
The compound (IV) prepared in example 2 was dissolved in dimethyl sulfoxide (DMSO) to prepare sample solutions having concentration gradients of 5, 15, 25, 35, 45, 60, 75, 90, 105, and 120mmol/L, respectively, which was designated as sample 1.
(2) Method for testing and detecting monoamine oxidase-A inhibitory activity of compound (IV)
To an EP tube containing 386 μ L of A boric acid buffer solution (pH 8.4), 4 μ L of monoamine oxidase-A (MAO-A) and 4 μ L of sample 1 prepared in step (1) were added, respectively, mixed, and the mixture was reacted in A water bath at 38 ℃ for 2 hours, and then to the above EP tube, 2 μ L of probe 7- (3-aminopropoxy) -4-methylcoumarin (10mmol/ml) represented by formulA (V) and 4 μ L of bovine serum albumin (bsA) were added, respectively, and the reaction was continued in A water bath at 38 ℃ for 2 hours. Simultaneously with this, the enzyme activity of the enzyme without inhibitor was measured by adding 4. mu.L of monoamine oxidase-A (MAO-A) to an EP tube containing 390. mu.L of boric acid buffer (pH 8.4), reacting in A38 ℃ water bath for 2 hours, and then adding 2. mu.L of probe (10mmol/ml) and 4. mu.L of BSA, and reacting in A38 ℃ water bath for 2 hours.
Finally, 100. mu.L of each EP tube (microcentrifuge tube) was placed in a 96-well plate and the sample was examined with a full-function spectrofluorometer (. lamda.ex/. lamda.em. 365/460nm) (spectraMax M, molecular instruments, USA). Calculating the IC of sample 1 from the measured fluorescence values50The results of the test for inhibition of monoamine oxidase-A activity by Compound (IV) are shown in Table 1.
Half Inhibitory Concentration (IC) for inhibitory effect of Compound50) To indicate. IC (integrated circuit)50This is the concentration of inhibitor at which the "response" is inhibited by half, the greater the inhibitory potency of the compound, the lower the value.
IC50Can be calculated in the following way:
1) the average fluorescence intensity (F) of the enzyme-and-probe-only buffer was detected and calculatedM)；
2) Calculating the fluorescence intensity of each component enzyme containing different concentration gradient inhibitors (the background value is subtracted);
3) according to the fluorescence intensity of each component enzyme of the inhibitor with different concentration gradients, linear regression of the relation between the concentration (C) and the fluorescence intensity (F) of the inhibitor is carried out, and an equation is established: f ═ aC + b (equation coefficients a and cut squat b are determined by regression lines);
4) according to the equation, F is 1/2FMThe corresponding inhibitor concentration at which the inhibition rate was 50% was determined as IC50。
Table 1 inhibitory Activity of Compound (IV) prepared in example 2 on monoamine oxidase A
| Compound | MAO-A IC50(μM) |
| IV | 1.079 |
As can be seen from Table 1, compound (IV) has a strong inhibitory activity against monoamine oxidase A.
Claims (7)
1. A monoamine oxidase A inhibitor of formula (IV),
2. a process for the preparation of a monoamine oxidase a inhibitor of formula (IV) according to claim 1, characterized in that it comprises the following steps:
the compound shown as the formula (III) is used as a reaction raw material, Ru/C is used as a catalyst, and NaIO is added4The monoamine oxidase A inhibitor shown in formula (IV) is obtained by carrying out reaction at room temperature by using water as a solvent as an oxidant and carrying out post-treatment on a reaction solution after the reaction is finished; the dosage of the Ru/C is 0.5-2% of the dosage of the compound shown in the formula (III) in terms of the dosage of the Ru; the NaIO4The amount of the substance (B) is 50 to 150% of the amount of the substance of the compound represented by the formula (III);
3. a process for the preparation of a monoamine oxidase a inhibitor of formula (IV) according to claim 2, characterized in that: the amount of Ru/C is 1% of the amount of substance of the compound represented by the formula (III) based on the amount of substance of Ru.
4. A process for the preparation of a monoamine oxidase a inhibitor of formula (IV) according to claim 2, characterized in that: the NaIO4The amount of substance (b) is 110% of the amount of substance of the compound represented by the formula (III).
5. A process for the preparation of a monoamine oxidase a inhibitor of formula (IV) according to claim 2, characterized in that: the volume usage amount of the water is 3-5 mL/mmol based on the amount of the compound shown in the formula (III).
6. A process for the preparation of a monoamine oxidase a inhibitor of formula (IV) according to claim 2, characterized in that: the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, the reaction solution is filtered, washed by dichloromethane, the filtrate and the washing solution are combined, washed twice by saturated sodium chloride solution, and dehydrated by anhydrous sodium sulfate, the solvent is removed by evaporation and dried, and the target product shown in the formula (IV) is obtained.
7. Use of a monoamine oxidase A inhibitor according to claim 1 for the preparation of a medicament for inhibiting monoamine oxidase A activity.
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